MXPA04002034A - Cyclic indole and heteroindole derivatives, the production and use thereof as medicaments. - Google Patents

Abstract

The invention relates to novel substituted, annelated indole and heteroindole derivatives of general formula (I), to tautomers, stereoisomers, mixtures and pharmaceutically acceptable salts thereof and to the production and use thereof as medicaments, in particular as anti-tumour agents in mammals, in particular humans.

Description

CYCLIC DERIVATIVES OF INDOL AND HETEROINDOL, ITS OBTAINING AND ITS USE AS MEDICINES DESCRIPTION OF THE INVENTION This invention relates to novel substituted derivatives of indole and heteroindole of the formula I their tautomers, their stereoisomers, their mixtures and their pharmaceutically acceptable salts, their preparation and their use as medicaments, in particular as antitumor agents, in mammals and in particular in man. the German patent application dated April 28, 2000 (Patent ASTA Medica AG with Privatdozent Dr. Mahboobi) describes a process for preparing 2-acylindoles by means of the corresponding 2-lithioindoles. Theophil Eicher and Ralph Rohde, Synthesis 1985, pp. 619-625, describes the preparation of 1,2-diphenyl-3a-azacyclopenta [a] inden-3-on. A medical application of the aforementioned compound is not described or suggested. According to one aspect of this invention, compounds of formula I are provided wherein R 1 is hydrogen, aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, heteroaryl of 1 to 13 carbon atoms which contains at least 1 to 4 of N, H, 0 or S as ring members and is unsubstituted or substituted wholly or partially by identical or different substituents, cycloalkyl of 3 to 8 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, or alkyl from 1 to 20 carbon atoms straight or branched chain which is unsubstituted or substituted completely or partially by identical or different substituents; A, B, C or D independently of each other are a nitrogen atom or a carbon atom substituted by R2-R2, R3, R4 and R5 independently of each other are a pair of free electrons (if the binding partner A, 33, C or D are a nitrogen atom), hydrogen, halogen, cyano, nitro, hydroxyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms which is substituted by one or more halogen atoms, straight or branched chain 1 to 6 carbon alkoxy, straight or branched chain 1 to 6 carbon alkoxy which is substituted by one or more halogen atoms, alkylenedioxy 1 to 6 carbon atoms straight or branched chain, alkylcarbonyloxy of 1 to 6 carbon atoms, alkoxycarbonyloxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, carboxyl, alkylcarboxylate of 1 to 6 carbon atoms, carboxamide, N-alkylcarboxamide of 1 to 6 carbon atoms, N, -di-alkylcarboxamide of 1 to 6 carbon atoms, alkoxy (of 1 to 6 carbon atoms) -alkyl from 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, wherein the two radicals of 1 to 6 carbon atoms together can form a ring which optionally contains one or more than NH, N-alkyl of 1 to S carbon atoms, O or S, aryl of 6 to 14 carbon atoms, aryloxy of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkoxy (of 1 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, hydroxyl, wherein the two directly adjacent radicals can be linked together; R6 is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, heteroaryl of 1 to 13 carbon atoms which contains at least 1 to 4 of N, KfH, and S as ring members and is unsubstituted or substituted wholly or partially by identical or different substituents, cycloalkyl of 3 to 8 carbon atoms, which is unsubstituted or substituted wholly or partially by identical or different substituents, alkyl of 1 to 20 carbon atoms straight or branched chain which is unsubstituted or substituted wholly or partially by identical or different substituents, wherein the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, carboxyl, alkyl of 1 to 6 carbon atoms which is substituted by one or more identical halogen atoms or different, alkoxy of 1 to 6 carbon atoms which is substituted by one or more identical or different halogen atoms, alkenyl of 2 to 6 carbon atoms of straight or branched chain, alkynyl of 2 to 6 carbon atoms of chain linear or branched, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkoxy of 1 to 6 carbon atoms, alkylenedioxy of 1 to 6 carbon atoms of straight or branched chain, alkoxy (from 1 to 6 a t carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of G to 14 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl (of 6 to 14 atoms) of carbon) -alkoxy (of 1 to 4 carbon atoms) -alkyl of 1 to 6 carbon atoms; X is a carbonyl group (C = 0), sulfoxide (S = 0) or sulfonyl (S02); Y is an oxygen atom or a nitrogen atom substituted by the radical R7 (NR7), wherein: R7 is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted completely or partially by identical or different substituents, heteroaryl from 1 to 13 carbon atoms, which contains at least one to four of N, NH, 0 or S as ring members and is unsubstituted or substituted completely or partially by identical or different substituents, cycloalkyl of 3 to 8 atoms of carbon which is unsubstituted or substituted wholly or partially by identical or different substituents, straight or branched chain alkyl of 1 to 20 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, wherein Identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms, carboxyl, alkyl of 1 to 6 carbon atoms which is substituted by one or more identical or different halogen atoms, alkoxy of 1 to 6 carbon atoms which is substituted by one or more atoms of identical or different halogen atoms, straight or branched chain 2 to 6 carbon alkenyl, straight or branched chain alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms straight-chain or branched carbon, straight-chain or branched-chain alkylene dioxycarbons of 1 to 6 carbon atoms, alkoxy (of 1 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms, monoalkylamino of 1 to 6 carbon atoms of carbon linear or branched chain, dialkylamino of 1 to 6 carbon atoms straight or branched chain wherein the two radicals of 1 to 4 carbon atoms together can form a ring which optionally contains one or more of H, N-alkyl of 1 to 6 carbon atoms, O or S, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkoxy (of 1 to 4 carbon atoms) carbon) -alkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms or alkoxycarbonyl of 1 to 6 carbon atoms; n is 0 or 1, with the proviso that if n = 0, Z is a carbon atom substituted by the radical R8 (C-R8) wherein R8 is aryl of 6 to 14 carbon atoms which is unsubstituted or fully or partially substituted by identical or different substituents, heteroaryl of 1 to 13 carbon atoms which contains at least 1 to 4 of N, NH, 0 or S as ring members and is unsubstituted or substituted wholly or partially by substituents identical or different, cycloalkyl of 3 to 8 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, straight or branched chain 1 to 20 carbon atoms, which is unsubstituted or substituted or partially by identical or different substituents, wherein the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, alkyl of 1 to 6 carbon atoms, oxy of 1 to 6 carbon atoms, carboxyl, alkyl of 1 to 6 carbon atoms which is substituted by one or more identical or different halogen atoms, alkoxy of 1 to 6 carbon atoms which is substituted by one or more identical or different halogen atoms, straight-chain or branched alkenyl of 2 to 6 carbon atoms, straight-chain or branched-chain alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 6 atoms straight-chain or branched carbon, straight-chain or branched-chain alkylenedioxy, straight-chain or branched-chain alkylthio, C 1-6 alkylsulfinyl with 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, arylthio of 6 to 14 carbon atoms, arylsulfinyl of 6 to 14 carbon atoms, arylsulfonyl of 6 to 14 carbon atoms, alkoxy (of 1 to 6 carbon atoms) -alkyl 1 to 6 carbon atoms, straight or branched chain monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms straight or branched chain wherein the two radicals of 1 to 4 carbon atoms together can form a ring which optionally contains one or more of NH, N-alkyl of 1 to 6 carbon atoms, 0 or S, aryl of 6 to 14 carbon atoms, aryloxy of 6 to 14 carbon atoms, aryl (of 6 to 14) carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkoxy (of 1 to 4 carbon atoms) -alkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, mono-N-alkylcarbonylamino of 1 to 6 carbon atoms of straight chain or branched, di-N, N-alkylcarbonylamino of 1 to 6 carbon atoms straight or branched chain, mono-Nalkoxycarbonylamino of 1 to 6 carbon atoms straight or branched chain, di-N, N-alkoxycarbonylamino of 1 to 6 atoms straight or branched chain carbon, N-alkyl (1 to 6 carbon atoms) -carbonylamino-N-alkylamino of 1 to 6 carbon atoms, straight or branched chain, or N-alkoxy (from 1 to 6 carbon atoms) -carbonylamino-N-alkylamino of 1 to 6 carbon atoms straight or branched chain; and where, if n = 1, Z is a nitrogen atom; or a tautomer, a stereoisomer, a mixture or a pharmaceutically acceptable salt thereof. According to a further aspect of the present invention, there are provided compounds which are characterized in that R is hydrogen, R 2, R 3, R 4 and R 5 independently of each other are hydrogen, halogen or alkoxy of 1 to 6 carbon atoms, R 6 is alkyl from 1 to 20 carbon atoms straight or branched chain which is unsubstituted or substituted wholly or partially by identical or different substituents or is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by identical substituents or different from the group consisting of alkoxy of 1 to 6 carbon atoms and halogen, Y is an oxygen atom or the radical N-7, wherein R7 is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted totally or partially by identical or different substituents, X is carbonyl (C = 0), Z is a nitrogen atom and n = 1. According to a further aspect of the invention, compounds are provided which are characterized in that l is hydrogen, R2, R3, R4 and R5 independently of each other are hydrogen, halogen or alkoxy of 1 to 6 carbon atoms, R6 is straight or branched chain alkyl of 1 to 20 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents or is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by substituents identical or different from the group consisting of alkoxy of 1 to 6 carbon atoms and halogen, n = 0, Z is the radical C-R8, wherein R8 is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by substituents identical or different from the group consisting of 1-alkoxy; to 6 carbon atoms and halogen, and X is carbonyl (C = 0). According to a further aspect of the invention, the compounds mentioned before according to the invention are provided for use as medicaments. According to a further aspect of the invention, there is provided the use of one of the compounds mentioned before according to the invention for controlling tumor disorders in mammals, in particular in man. According to a further aspect of the invention, medicaments are provided which comprise at least one of the compounds mentioned above, according to the invention together with pharmaceutically acceptable auxiliaries, diluents or carriers. According to a further aspect of the invention, there is provided a process for preparing the compounds of the formula I according to the invention: wherein A, B, C, D, R1, R2, R3, R4, R4, R5, X, Y, Z and n are as defined in claim 1, characterized in that: a) the ketone is reacted the formula with aa) oxime, or bb) hydrazine derivative H2N-NH-R7 wherein R7 is as defined in claim 1, and the resulting product is cyclized with an activated carbonyl, a sulfoxide or sulfonyl derivative or reacted with : ce) a phenylacetic acid derivative XI-CO-CH2-R8, wherein XI is a suitable leaving group, such as halogen or alkoxy of 1 to 2 carbon atoms, and R8 is as defined in claim 1, followed by by cyclization in the presence of base. The compounds of the formula I according to the invention can be obtained by methods known per se. A suitable method is, for example, the procedure described below: a) the reaction of an indole or heteroindole compound, if appropriate, with a suitable nucleofugic leaving group E with organometallic compounds is provided: wherein R 1, R 2 , R3, R4, R5, R6, A, B, C and D are as defined above, R9 is hydrogen, straight or branched chain alkylcarbonyl of 1 to 6 carbon atoms which is unsubstituted or substituted by one or more halogen atoms, straight chain alkoxycarbonyl of 1 to 6 carbon atoms 0 branched, aryl (from 6 to 14 carbon atoms) -alkyl 1 carbon atom substituted, alkylsulfonyl of 1 to 6 carbon atoms straight or branched chain or arylsulfonyl of 6 to 14 carbon atoms which is unsubstituted or substituted by alkyl of 1 to 6 carbon atoms, E is OH, a halogen atom, for example a fluorine, chlorine or bromine atom, alkoxy of 1 to 6 carbon atoms, imidazole and M is Li, Mg-R10, wherein RIO is a halogen atom, for example a chlorine atom, bromine or iodine; for n = 0: bl) the reaction of the 2-acylindole heteroindole compounds with a reagent having suitable nucleophonic leaving groups, if appropriate with simultaneous or previous separation of the substituent R9 at the indole nitrogen atom: wherein R 1, R 2, R 3, R 4, R 5, R 6, R 8, R 9, A, B, C, D, E and X are as defined above, the) reaction of the 2-acylindole or heteroindole compounds with a base, preferably sodium hydride: wherein R 1, R 2, R 3, R 4, R 5, R 6, R 8, A, B, C, D, E and X are as defined above, and Z is a carbon atom substituted by a radical R 8, for n = 1: b2) reaction of 2-acylindole heteroindole compounds with unsubstituted substituted primary amino derivatives: wherein: R1, R2, R3, R4, R5, R6, R9, A, B, C, D and Y are as defined above, Z is a nitrogen atom and RIO is hydrogen, alkyl of 1 to 6 atoms of straight or branched chain carbon, straight or branched chain alkyl of 1 to 6 carbon atoms, linear or straight chain alkyl of 1 to 6 carbon atoms; branched chain substituted by one or more halogen atoms, straight or branched chain alkoxy of 1 to 6 carbon atoms substituted by one or more halogen atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkoxy (1 to 6) carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkyl of 1 to € carbon atoms, aryl (of 6 to 14 atoms) carbon) -alkoxy (from 1 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms; c2) reaction of the indole or heteroindole compounds with a reagent having suitable nucleofugic leaving groups, if appropriate with simultaneous or previous separation of the substituent R9 at the indole nitrogen atom: R1, R2, R3, R4, R5, R6, R9, A, B, C, D and X are as defined above, Z is a nitrogen atom and RIO is a hydrogen atom, and Rll and R12, independently from each other, they are nucleofugic leaving groups, such as a halogen atom, for example a chlorine, bromine or iodine atom, alkoxy of 1 to 6 carbon atoms or imidazilide. However, the preparation is particularly advantageously carried out by reacting an indole-generated indole or heteroindol carboximidazolide of the formula II wherein: R1, R2, R3, R4, R5, R9, A, B, C and D are as defined in the foregoing, with Grignard reagents, reacting the indole heteroindole derivatives of formula III wherein: R1, R2, R3, R4, R5, R6, R9, A, B, C and D are as defined above, with hydroxylamine, cyclizing the indole or heteroindole derivatives of the formula IV in which : Rl, R2, R3, R4, R5, R6, A, B, C and D are as defined in the above, with?,? ' -carbonyldiimidazole to provide the indole or heteroindole derivatives of the formula V and cyclizing the indole or heteroindole derivatives of the formula III mentioned above, wherein R 1, R 2, R 3, R 4, R 5, R 6, A, B, C and D are as defined in the above and R 9 is an hydrogen, with unsubstituted or substituted phenylacetyl halides in the presence, for example, of sodium hydride as a base, to provide the indole or heteroindole derivatives of the formula VI.

The compounds used as starting materials, some of which are commercially available or are known from the literature, are obtained by methods known from the literature; In addition, its preparation is described in the examples. Known procedures of the literature are described, for example, in L. and M. Fieser, Organische Chemie [Organic Chemistry], second edition, 1979, pages 1417 to 1483 and in the literature mentioned therein, in the pages 1481-1483, in Houben-Weyl-Müller, Methoden der organischen Chemie [Methods of organic chemistry [and in Ullmanns Encyklopadie der technischen Chemie [Ullmann's Encyclopedia of Technical Chemistry]. the formula I can be separated into their enantiomers or into their diastereomers, so, for example, the resulting compounds of formula I which are present as racemates can be separated by methods known per se, and their enantiomers and the compounds of formula I having at least 2 asymmetric carbon atoms, due to their physicochemical differences can be separated by methods known per se, for example, by chromatography or fractional crystallization, in their diastereomers which, when obtained in racemic form, are then they can separate as mentioned in the above in the enantiomeros. The separation of enantiomers is preferably carried out by separation by column chromatography on chiral phases, either by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives such as, for example, esters or amides with the racemic compound. In addition, the resulting compounds of the formula I can be converted into its salts, in particular for pharmaceutical application in its pharmacologically and physiologically acceptable salts, using inorganic or organic acids. Suitable acids for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. In addition, the compounds of the formula I, if they contain an acidic group such as a carboxyl group, can be converted, if desired, into their salts, in particular for pharmaceutical applications, into their physiologically acceptable salts using inorganic or organic bases. Suitable bases for these purposes are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. The invention is illustrated in more detail in the following by means of examples; however, the invention is not limited to said examples. General procedures for preparing the 2-acylindoles according to the invention.

Method A) Isolation of the imidazol-1-yl (lH-indol-2-yl) methanones and subsequent reaction with organometallic reagents. With stirring at room temperature, a solution of 72 mmoles (11.67 g, 1.2 equivalents) of?,? 'Is added dropwise. -carbonyldiimidazole in 250 ml of tetrahydrofuran, to a solution of 60 mmol (11.47 g) of 5-methoxyindole-2-carboxylic acid in 200 ml of tetrahydrofuran, for a period of 60 minutes. After an additional 15 minutes of stirring the solvent is removed using a rotary evaporator and the residue is recrystallized from 220 ml of tetrahydrofuran: hexane = 3: 2. This affords orange-brown solid imidazol-1-yl- (5-methoxy-1H-indol-2-yl) methanone. P.f .: > 300 (decomposition) At 0 ° C, 2.2 equivalents of the organometallic compound are dropwise added to a solution of 1 equivalent of imidazol-1-yl- (5-methoxy-1H-indol-2-yl) methanone in tetrahydrofuran (3 ml / mmol) of so that the internal temperature does not exceed 5 ° C. The conversion of the reaction is monitored by thin layer chromatography (mobile phase, ethyl acetate: hexane = 1: 1). After the reaction has ended, water (10 ml / mmol) is added to the reaction solution and the pH is adjusted to 6 using concentrated hydrochloric acid. The organic phase is separated and the aqueous phase is extracted three times with ethyl acetate (in each case, 2 ml / mmol). The combined organic phases are dried over magnesium sulfate and the solvent is then removed using a rotary evaporator and the residue is crystallized from alcohol.

Example Al: Al reactant: Methylmagnesium chloride, 3.0 M solution in tetrahydrofuran 1- (5-methoxy-lH-indol-2-yl) ethanone P.f .: 164-167 ° C (2-propanol) Example S2: Reagent A2: Phenylmagnesium bromide, 3.0 M solution in diethylether (5-methoxy-1H-indol-2-yl) phenylmethanone Mp .: 164-166 ° C (n-butanol) Example A3: Reagent? 3: 3-methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran (5-methoxy-lH-indol-2-yl) - (3-methoxyphenyl) methanone Mp .: 143-145 ° C (n-butanol) Example A4: Reagent A4: 3-methoxyphenylmagnesium bromide, 0.5 M solution in tetrahydrofuran (5-methoxy-lH-indol-2-yl) - (4-methoxyphenyl) methanone P.f .: 155-158 ° C (n-butanol) Example A5 Reagent A5: 3-Chlorophenylmagnesium bromide, 1.0 M solution in diethylether (4-chlorophenyl) - (5-methoxy-lH-indol-2-yl) methanone Mp .: 190-192 ° C (n-butanol) Example A6: Reagent A6 tetrahydrofuran methoxy-1H-indol-2-yl) thiophen-2-ylmethanone. : 152-154 ° C (n-butanol) Method B) Variant that is carried out in a container: Synthesis of imidazol-l-yl (lH-indol-2-yl) methanones and subsequent reaction in situ with organometallic reagents It is added dropwise, with stirring and under an inert gas atmosphere , a solution of 26 mmoles (1.05 equivalents) of?,? ' -carbonyldiimidazole in tetrahydrofuran (3 ml / mmol), at room temperature, to a solution of 25 mmoles of an indole-2-carboxylic acid in tetrahydrofuran (2 ml / mmol) over a period of 20 minutes. After a further agitation period of 60 minutes, the reaction solution is cooled to 0 ° C and 3.5 equivalents of the organometallic compound are added dropwise so that the internal temperature does not exceed 5 ° C (about 60 minutes). The conversion of the reaction is monitored by thin layer chromatography (mobile phase of ethyl acetate: hexane = 1: 1). After the reaction has ended, water (10 ml / mmol) is added to the reaction solution and the pH is adjusted to 6 using concentrated hydrochloric acid. The organic phase is separated and the aqueous phase is extracted three times with ethyl acetate. In each case, 2 ml / mmol. The combined organic phases are dried over magnesium sulfate and the solvent is then removed using a rotary evaporator and the residue is crystallized from alcohol.

Example Bl: Initial material: Indole-2-carboxylic acid Reactive Bl: 2-methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran (lH-indol-2-yl) - (2-methoxyphenyl) methanone P.f .: 129-130 ° C (ethanol: water = 4: 1) Example B2: Initial material: Indole-2-carboxylic acid Reagent A3: 3-methylphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran (lH-indol-2-yl) - (3-methoxyphenyl) methanone Mp .: 119-121 ° C (3-propanol) Example B3 Initial material: 5-methoxyindole-2-carboxylic acid Reagent Al: Methylmagnesium chloride, 3.0 M solution in tetrahydrofuran 1- (5-methoxy-lH-indol-2-yl) ethanone P.f .: 164-167 ° C (2-propanol) Example B: Starting material: 5-methoxyindole-2-carboxylic acid Reagent B4: Ethylmagnesium chloride, 3.0 M solution in tetrahydrofuran 1- (5-methoxy-lH-indol-yl) ropan-1-one Pf: 173-175 ° C (2-propanol) Example B5: Initial material: 5-methoxyindole-2-carboxylic acid Reagent? 2: Phenylmagnesium bromide, solution 3.0 in diethylether methoxy-1H-indol-2-yl) phenylmethanone. : 164-165 ° C (n-butanol) Example B6: Starting material: 5-Methoxyindole-2-carboxylic acid Reagent? 3: 3-methoxyphenylmagnesium bromide, 1.0 M solution in tetrahydrofuran (5-methoxy-lH-indol-2-yl) - (3-methoxyphenyl) methanone P.f .: 143-145 ° C (n-butanol) General procedure for preparing oxadiaza derivatives, according to the invention Method C) Preparation, isolation and purification of indole-2-yloximes and subsequent reaction with α, β-carbonyldiimidazole Cl) General synthesis of indole-2-yloximes: They are added 1.5 equivalents of solid hydroxylamine hydrochloride and then, dropwise with stirring, over a period of 5 minutes, 3.0 equivalents of potassium hydroxide, 0.5 M in methanol, to a suspension of 1 equivalent of 2-acylindole prepared in accordance with Method A or B in ethanol (10 ml / mmol). The reaction solution is heated under reflux for 3-9 hours (monitored by CCD) and, after cooling to room temperature, it is poured into water (150 ml / mmol) and adjusted to pH 6 using hydrochloric acid (10% by weight). Water) . The precipitate that forms is isolated and recrystallized from alcohol: water. If no precipitate is formed, the organic phase is separated, the aqueous phase is extracted three times with ethyl acetate (in each case, 2 ml / bouquet), the combined organic phases are dried over magnesium sulfate, the solvent is separated using a rotary evaporator and the product is subsequently purified by recrystallization, or the crude product is further reacted according to C2 (method D).

Example Cl .1 (D-81687): Initial material Al: 1- (5-methoxy-1H-indol-2-yl) ethanone 1- (5-methoxy-lH-indol-2-yl) ethanone oxime P.f. : 148-150 ° C (2-propanol) Example C1.2 (D-81690) Starting material B4: 1- (5-methoxy-lH-indol-2-i1) propan-1-one 1- (5-methoxy-lH-indol-2-yl) propan-l-one oxiraa P.f .: 163-165 ° C (2-propanol) Example Cl .3 (D-70258): Initial material A2 (5-methoxy-1H-indol-2-yl) phenylmetanone (5-methoxy-lH-indol-2-yl) phenylmethanine oxime P.f .: 150-152 ° C (2-propanol: gua = 2: 3) Example C1.4 (D-70745) Starting material A5: (4-chlorophenyl) - (5-methoxy-lH indol-2-yl) methanone (4-chlorophenyl) - (5-methoxy-lH-indol-2-yl) methanone oxime. Crude product (purity determined by CLAR: 81%) Reaction of lH-indole-2-ylmetanone oximes with N, '-carbonyldiimidazole 1.2 equivalents of solid N, N-carbonyldiimidazole are added to a solution of 1 equivalent of lH-indol-2-ylmetanone oxime in tetrahydrofuran (30 ml / mmol ) and the mixture is heated under reflux for 1-3 hours (monitored by CCD). After cooling to room temperature, the reaction solution is poured into water (400 ml / mmol) and the precipitate that forms is isolated and crystallized from alcohol. If no precipitate is produced, the organic phase is separated and the aqueous phase is extracted three times with ethyl acetate (in each case, 2 ml / mmol). The combined organic phases are dried over magnesium sulfate and the solvent is then removed using a rotary evaporator and the product is purified by column chromatography on silica gel or under atmospheric pressure (mobile phase, ethyl acetate = 1: 3). ).

Example C2.1 (D-81688): Initial material Cl. 1: 1- (5-methoxy-lH-indol-2-i1) ethanone oxime 3-methyl-l, 2, 5-oxadiazino [4,5-a] (5-methoxyindole) -6-one P.f .: 217-220 ° C (2-propanol) Example C2.2 (D-81691): Initial material Cl. 2: 1- (5-methoxy-lH-indol-2-yl) propan-l-one oxime 3-ethyl-l, 2, 5-oxadiazino [4,5-a] (5-methoxyindole) -6-one P.f .: 208-212 ° C (n-butanol) Example C2.3 (D-70260): Starting material Cl. 3: (5-methoxy-lH-indol-2-yl) phenylmethanone oxime 3 - . 3-phenyl-1,2,5-oxadiazino [4,5-a] (5-methoxyindole) -6-one P.f .: 198-200 ° C (n-butanol) Method D) Direct reaction of lH-indol-2-ylmetanone oximes prepared with?,? ' -carbonyldiimidazole The following oxadiaza derivatives are synthesized according to the Cl method, but without purification, and further react according to C2.

Example DI (D-81362): Initial material Bl (lH-indol-2-yl) - (2-methoxyphenyl) methanone 3- (2-methoxyphenyl) -1,2,5-oxadiazino [5-a] indol-6-one Pf: 160-162 ° C (column chromatography) Example D2 (D-81361) Starting material B2 (lH -indol-2-yl) - (3-methoxyphenyl) methanone 3- (3-methoxyphenyl) -1,2,5-oxadiazino [4,5-a] indol-6-one P.f .: 129-130 ° C (column chromatography) Example D3 (D-81462) Starting material A3 (5-methoxy-lH-indol-2-yl) - (3-methoxyphenyl) methanone 3- (3-methoxyphenyl) -1,2,5-oxadiazino [4,5-a] (5-methoxyindole) -6-one P.f .: 171-173 ° C (ethanol) Example D4 (D-70744): Initial material A5: (4-chlorophenyl) - (5-methoxy-lH-indol-2-yl) methanone 3- (4-chlorophenyl) -1,2,5-oxadiazin [4,5-a] (5-methoxyindole) -6-one P.f. : 227-230 ° C (n-butanol) The following compounds, according to the invention (examples numbers 1 to 324) can also be prepared according to synthesis methods C and D mentioned above, from acid derivatives indole-2-carboxylic, with different substituents: Initial material: 4 Product: (n = 1, Z = N) 4 - - - Analogously, according to the general procedure E which is provided in the following, it is possible to prepare the following compounds according to the invention (examples 325 to 2634): Examples Nos. 325-654: A, C, D, R, Rl, R6 and X have the meanings indicated in examples numbers 1-324 indicated above, and And in each case it is NH; Examples Nos. 655-984: A, C, D, R, Rl, R6 and X have the meanings indicated in examples numbers 1-324 indicated above, and And in each case it is N-CH3; Examples Numbers 985-1314: A, C, D, R, Rl, R6 and X have the meanings indicated in examples numbers 1-324 indicated above, and And in each case it is N-C2H5; Examples Numbers 1315-1644 A, C, D, R, R1, R6 and X have the meanings indicated in examples numbers 1-324 indicated above, and And in each case it is N-C6H5 Examples Numbers 1645-1974: A, C, D, R, Rl, R6 and X have the meanings indicated in examples numbers 1-324 indicated above, and And in each case it is N-2 - (CH30) -C6H4; Examples Nos. 1975-2304: A, C, D, R, R1, R6 and X have the meanings indicated in examples numbers 1-324 indicated above, and And in each case it is N-3 - (CH30) -CSH4; Examples Numbers 2305-2634 A, C, D, R, R1, R6 and X have the meanings indicated in the examples numbers 1-324 indicated above, and And in each case it is N-4- (CH30) -C6H4.

E) General procedure for preparing the 1,2,4-triazino [4,5-a] indole derivatives according to the invention. 2 equivalents are added, corresponding to the monosubstituted hydrazine derivative and glacial acetic acid (0.5 ml / mmol) to a suspension of 1 equivalent of 2-acylindole prepared according to method A or B in n-butanol (10 ml / mmol). ) and the mixture is heated under reflux for 16 hours (monitored by CCD). After cooling to room temperature, the reaction solution is poured into water (150 ml / mmol), the organic phase is separated and the aqueous phase is extracted three times with ethyl acetate (10 ml / mmol). The combined organic phases are dried over magnesium sulfate and the solvent is carefully removed using a rotary evaporator and the crude product is dissolved in tetrahydrofuran (7.5 ml / mmol). 1.3 equivalents of?,? ' -carbonyldiimidazole and then 2.1 equivalents of sodium hydride (75% dispersion force in white oil), and after 2 hours at room temperature the mixture is heated under reflux for 48 hours. After cooling to room temperature, the reaction solution is poured into water (150 ml / mmol), the solid is isolated and the product is purified by column chromatography on silica gel under atmospheric pressure (mobile phase, diethyl ether: hexane = 1.2).

Example (D-70746): Initial material A5: (4-chlorophenyl) - (5-methoxy-lH-indol-2-yl) methanone Reagent El: Phenylhydrazine 2 - . 2-phenyl-6- (4-chlorophenyl) -1,2,4-triazino [4,5-a] (5-methoxyindole) -3-one P. f. : 155-158 ° C.

F) General procedure for preparing pyrrolo [1,2-a] indole derivatives according to the invention 1.1 equivalents of solid sodium hydride (dispersion 60-75% in mineral oil) are added a little at a time. a solution of 1 equivalent of 2-acylindole prepared according to method A or B in N, N-dimethylformamide (10 ml / mmol) and after 5 minutes of stirring at room temperature, the mixture is heated to 90 ° C during one hour. The mixture is then cooled again to room temperature, 1.1 equivalents of the substituted phenylacyl halide are added dropwise and the mixture is heated once more at 90 ° C for 3 to 8 hours (monitored by CCD). After cooling to room temperature, the reaction solution is poured into water (150 ml / mmol) and the precipitate that forms is isolated and purified by column chromatography on silica gel under atmospheric pressure mobile phase, diethyl ether: hexane = 1 :3).

Example Fl (D-80786): Initial material A5: (4-chlorophenyl) - (5-methoxy-lH-indol-2-yl) methanone 1- (4-chlorophenyl) -6-methoxy-2-phenyl-3a-aza-cyclopenta [a] inden-3-one P.f. : 152-155 ° C Example F2 (D-80815) Starting material B6: (5-methoxy-lH-indol il) - (3-methoxyphenyl) methanone 6-methoxy-1- (3-methoxyphenyl) -2-phenyl-3a-aza-cyclopenta [a] inden-3-one P.f. : 111-113 ° C.

Example F3 (D-80816): Starting material B6: (5-methoxy-lH-indol-2-yl) - (3-methoxyphenyl) methanone 6-methoxy-l, 2-bis (3-methoxyphenyl) -3a-aza-cyclopenta [a] inden-3 -one P.f. : 112-114 ° C Example F4 (D-80819): Starting material A4: (5-methoxy-1H-indol-2-yl) - (4-methoxyphenyl) methanone 2- (4-fluorophenyl) -6-methoxy-1- (4-methoxyphenyl) -3a-azacyclopenta [a] inden-3-one Pf: 157-160 ° C The following compounds according to the invention (examples numbers 2635) to 3842) can be prepared according to synthesis procedure F above, from the indole-2-carboxylic acid derivatives, with different substituents.

Initial material: 4 Product: (n = 0, Z = C-R8) 4 2670 CH CH CH H H 2- ICH30) -CBH «C« H5 C (O) 2671 CH CH CH H 2- (C¾0) -C3H «2- (C3JjO) -CiH« C (O) 2672 CH H CH H H 2- < a¼0) -. ¾¾ 3-. { eH30) -CeH «C (O) 2673 CH CH CH H 2- (C¾0) -C6H4 4- (CH30) -Ce¾ C (O) 2674 CH CH CH B 2- (CH30) -C5H "2.3- (CH30) 2-C¾H3 C (O) 2675 CH CH CH H 2- (CH.}. 0) -C6H4 2.4- (CH30) j-C6H3 C (O) 2676 CH CH CH H H 2- (CHjO) -C6¾ 3.4- "2¾0) 2- < ¾? 3 C (O) 2677 CH CH CH H 2- (O¾0) -C5H (3.5- (CH30) 2-C6H3 C (O) 2678 CH CH CH H 2- (CH 2 O) -C 3 H 4 3,4,5- (CH 30) 3-¾H 2 C (O) 2679 CH CH CH H H 3- (C¾0> -CeH4 CH3 C (O) 2680 CH CH CH H H 3- (OÍ30) -CfiHí C2H5 C (0) 2681 CH CH CH H H 3- (CH30) -Ce¾ CSHS C (O) 2682 CH CH CH H 3- (CH 30) -C 3 H 4 2- (CH 30) -CeH 4 C < 0) 2683 CH CH CH H 3- (CHaO> - C6H | 3- (CH30) -CSH «C (O) 2684 CH CH CH H H 3-. { CH30) -CEH4 4- (CH3O) -C6H «C (O) 2685 CH CH CH H 3 - (? ¾0) - (¼¾ 2,3- (CH30) 2-C6H3 C (O) 2686 CH CH CH H H 3- (C% O) -C6H < 2,4- (CH30) 2-C6H3 C (0 > 2687 CH CH CH H 3- (CH30) -Cfi¾ 3.4- (CH30) 2-C6H3 C { 0) 2688 CH CH CH H H 3- (C¾0) -CsH 4 3.5- < CH30) 2-C6H3 C (O) 2689 CH CH CH H H 3- < C¾0) -CBHi 3,4,5- (CH30) 3-C3H2 C (O) 2690 CH CH CH H H 4- < CH30) -C6H4 CH3 C { 0) 2691 CH CH CH H H 4- < CH30) -C6¾ CjHs C (0) 2692 CH CH CH H H 4- (CH 3 O) -CG¾ ¾HS C (O) 2693 CH CH CH H H 4- (CH 30) -C 4 H 4 2- (CH 3 O) -CSH 4 C (O) 2694 CH CH CH H H 4- < CHjO) -C6H4 3- (CHjO) -C6H4 C (O) 2695 CH CH CH H 4- (CH 30) -CgH 4 4- (CH 30) -CfiH, C (O) 2696 CH CH CH H 4- (CH 30) -CsCl 4 - (CH30) 2-C6H3 C (0) 2697 CH CH CH H 4- (CH 3 O) -C 6 H * 2,4- (CKs 0) 2-C 3 Hs C (O) 2698 CH CH CH H 4- (CH30) -C3H4 3.4- (CH30) a-C6H3 C (O) 2699 CH CH CH H 4- (CH 30) -CiH 4 3,5- (CH 30) 2-C 6 H 3 C (0 > 2700 CH CH CH H H 4- (CHjO) -CtHí 3,4,5-. { € 3? 30) 3-a6? 3 C (O) 2701 CH CH CH H H 2.3- (CHjC »a ~ CH3 CIO) CeH3 2702 CH CK CH H H 2.3-. { CH30) jr C2HS C (O) C6H3 - - - - - - - - - - - - - - 2889 CK CH CH 5-CH30 H CjHs C2¾ C (O) 2890 CH CH CH 5-CH3O H C.H3 C6HS C (O) 2891 CH CH CH 5-CH 3 O H C 2 H. 2- (C¾0) -C «H« CÍO) 2892 CH CH CH 5-C¾0 H ¾¾ 3- (CH30) -CeH, C (O) 2893 CH CH CH 5-C¾0 H < ¾Hs 4- (CH30) -C6H «C (O) 2894 CH CH CH 5-C¾0 H ¾¾ 2,3- (CH30) s-Ce¾ C (0) 2895 CH CH CH 5-CHjO H ¾¾ 2,4- (CH30) a-Ce-¼ C O) 2896 CH CH CH 5-CH3O H ¾¾ 3.4- (C¾0) a-C6H3 C < 0) 2897 CH CH CH 5-CH3O R CSH5 3.5- (CH30) 3-C3H3 C (O) 2898 CH CH CH 5-CH3O H ¾H5 3,, .5-. { GH30) 3-C6H2 C (0) 2899 CH CH CH 5-CHjO H C.HS CH3 C (O) 2900 CH CH CH 5 -CH3O H C | H5 C2H5 C (O) 2901 CH CH CH 5-CH3O H CBH5 C6¾ C (0) 2902 CH CH CH 5-CH3O H C6Hs 2- (CH30) -Cfi¾ C (0) 2903 CH CH CH 5-CH 3 O H C 6 HS 3- (CH 30) -Cs C < 0) 2904 CH CH CH 5-CH 3 O H 4- (CH 30) -C 6 H 4 C (O) 2905 CH CH CH 5-C¾0 H CSH5 2,3- (C¾0) 3-C6H3 CÍO) 2906 CH CH CH 5-C% 0 H < ¼¾ 2,4-. { CH30) 2-C6H3 C (O) 2907 CH CH CH 5-CH3O H 3.4-. { CH30) 2-C6H3 CÍO) 2908 CH CH CH 5-CHjO H CeHs 3,5 - (?? 3?)? - ¾¾ CÍO) 2909 CH CH CH 5-CH 3 O H C_H 5 3,4,5- (CH 30) 3-C 6 H 2 CIO) 2910 CH CH CH 5-CH3O H 2- (CH30) -C6H4 CH3 C (O) 2911 CH CH CH 5-CH3O H 2- (CH30) -CeH4 ¾H5 C (O) 2912 CH CH CH 5-CHjO H 2- (CH30) -CsHt C6¾ CÍO) 2913 CH CH CH 5-CH 3 O H 2- (CHjO) -C 6 H "2- (CH 30) -C 6 H 2 C (O) 2914 CH CH CH 5-C¾0 H 2- (CH30) -CeH4 3- (CH30) -C6B4 C (O) 2915 CH CH CH 5-CH3O H 2- (CH30> -C6H4 4- <CH30> -C6¾ C (O) 2916 CH CH CH 5-CH3O H 2- (C¾0) -C6¾ 2.3- (CH30) 2-CsH3 C (O) 2917 CH CH CH 5 -CH 3 O H 2- (C¾0) -CÉH 4 2r 4 - (CH 30) a-CíH 3 CÍO) 2918 CH CH CH 5-C¾0 H 2- (CHsOJ-CtH »3,4- (CH30) a-C3H3 C (O) 2919 CH CH CH 5 -CH3O H 2- (CH30) -C; 3.5- (CH30) a-CgHj CÍO) 2920 CH CH CH 5-CH 3 O H 2- (C¾0) -CÍH "3,4,5-. { CHjO) 3-C6H. CO) 2921 CH CH CH 5-CH3O 8. 3- (CH30) -C5H "C¾ 'CÍO) 2922 CH CH CH 5-CH 3 O H 3- (CH 30) -C_H «¾¾ C (O) 2923 CH CH CH 5-CH 3 O H 3- (CH 30) -C 3 H "2- (CH 30) -C 6 Ht C (O) 2924 CH CH CH 5-C% 0 H 3- (C¾0) -C6H «4-. { CH3O) -C6H «CÍO) - - - 9 - - - 3014 CH C CH 6-F H C2HS 2,4- (C¾0) 2-C6H3 C < 0) 3015 CH C CH 6-F H ¾¾ 3,4- (CHjOH-CeHj CÍO) 3016 CH C CH 6-F H ¾¾ 3,5- C¾0) a-C6H3 C (O) 3017 CH c CH 6 -F H CaHs 3,4,5- (CH30) 3-C6H2 C { 0) 3018 CH c CH 6-F H CtH5 CH3 CÍO) 3019 CH c CH 6-F H ¾¾ Ca¾ CÍO) 3020 CH c CH 6-F H CjHs CsHs C (O) 3021 CH c CH 6-F H CjHs 2-ÍCH30) -C8H4 CÍO) 3022 CH c CH 6-F H CtHs 3- (CH30) -Cj¾ C (0) 3023 CH c CH 6-F H c_¾ 4- (CH30) -C $ Hi C (O) 3024 CH c CH 6-F H C »H5 2.3- (CH30) j-CeH3 CÍO) 3025 CH c fell 6-F H C (H5 2,4- (CH30) 2-CeH3 C (O) 3026 CH c CH 6-F H CÍH5 3,4-. { CH30) 2-CsH3 CÍO) 3027 CH c CH 6-F H C6HS 3.5- (CH30) 2-C6H3 C (O) 3028 CH c CH 6 -F H 3,4,5- (CH30) 3-C6H2 CÍO) 3029 CH c CH, 6-F H 2- (CHjO) -C5H4 C¾ C (O) 3030 CH c CH 6-F H 2- < ? ¼0) -Ce¾ CjHs CÍO) 3031 CH c CH 6-F? 2- (CHsO) -C6H | C «H5 C { 0) 3032 CH c CH 6 -F · H 2 - (? ¾0) -¾¾ 2- (CH30) - < ¼¾ C (O) 3033 CH c CH 6 -F H 2- (CHjO) -CeHt 3- (CH30) -C6H | CO) 3034 CH c CH 6-F H 2- < CH, 0 > -CÍH < 4- (CH30) -CsH4 CÍO) 3035 CH c CH 6-F H 2 ~ (CH, 0) -C6¾ 2.3- (CH30) j-C3H3 C (O) 3036 CH c CH 6-F H 2- (C¾0) -C £ H «2,4-. { CH30) 2-C6H3 C (O) 3037 CH c CH 6 -F H 2- (CHjO) -CsH "3,4- (CH30) 2-C6H3 CÍO) 3038 CH c CH 6-F H 2 ~. { C¾0) ~ C.H «3,5-. { CH30) 2-C6H3 CÍO) 3039 CH c CH 6 -F H 2- (CH30) -C_H4 3,4,5-ÍCH30) 3-C6¾ CÍO) 3040 CH c CH 6-F H 3-. { OFFER-CsHt CH3 CÍO) 3041 CH c CH 6 -F H 3- tCH_0) -C6H. CaH5 C (O) 3042 CH c CH 6-F H 3- (CH30) -C6¾ C6¾ CÍO) 3043 CH c CH 6-F H 3- (C¾0) -C (H4 2- [CHiO) -CtUl CÍO) 3044 CH c CH 6 -F H 3- (CHsO) -C6H «3- (CH30) -CfB_ CÍO) 3045 CH c CH 6 -F H 3- (C¾0) -C6H4 4- (CH30) -C6H »CÍO) 3046 CH c CH 6-F H. 3- < CH30) -C6H "2.3-ICH30) 2-C < H3 C { 0) 3047 CH c CH 6-F H 3 - "% 0) -¾? 4 2,4- (CH30) í-C6H3 C (0) 3048 CH c CH 6 -F · H 3- (CH30) -CyH4 3.4- (CH30) 2-C6H3 C (O) 3049 CH c CH 6-F H 3-. { CH30) -C6H "3.5- (CH30) 2-C6H3 CIO) - - 3110 CH C CH 6-PH 3,4,5 (CH30) 3- 3- (CH30) -C6H4 C (O) CfH, 3111 CH C CH 6-FH 3,4,5 (CH30 > 3- 4- (C¾0) -CeH, C (0) Ce¾ 3112 CH C CH 6 -FH 3,4,5- (CH 3 O) 3- 2,3- { CH 30) a-CsH 3. C (O) CeHa 3113 CH C CH 6 -FH 3,4,5- (CH 3 O) 3- C (0) C; 3114 CH C CH 6 -FH 3,4,5- (CHsO) 3- 3,4- (CH30) 2-C6H3 C (0) Cf¾ 3115 CH C CH 6-FH 3,4,5 (C¾0) 3- 3,5-tCH30) a-CíH3 C (0) C6¾ 3116 CH C CH 6-FH 3,4,5- (a¾0) 3- 3,4,5- (CH30) 3-C6¾ C (O) C "H2 3117 CH CH C 7 -CH3 H e¾ CH3 C { 0) 3118 CH CH C 7 -CH 3 H c¾ c3¾ C { 0) 3119 CH CH C 7 -CHs H CH3 C6H5 C (O) 3120 CH CH C 7 -CH3 H c¾ 2- (C¾0) -C3H4 C (0) 3121 CH CH C 7 -CH 3 H CH 3 3- (CH 30) -C 3 C { 0) 3122 CH CH c 7 -CH 3 H CH 3 4-. { CH30) -C3H4. CO) 3123 CH CH C 7 -CH 3 H CH 3 2,3- (CH 30) 8-C 6 H 3 C { 0) 3124 CH CH c 7 -CH3 H CH3 2.4- (CH3Ó) j-C6Hj C (O) 3125 CH CH c 7-CH3 H CH3 3,4- (CH30) 2-CíH3 C (O) 3126 CH CH c 7 -CH3 'H CH3 3.5- (CHjO) 3-CsHs C (O) 3127 CH CH c 7 -CH3 H CH3 3,, 5- (CH30) 3-C6H2 C (0) 3128 CH CH c 7-CH3 H c2¾ CH3 C (O) 3129 CH CH c 7-CH3 H CaH5 (¾¾ C (O) 3130 CH CH c 7 -CH3 H C2H5 C, H5 C (O) 3131 CH CH c 7 -CH3 H C8H5 2- (CH30) -CeH «C { 0 > 3132 CH CH c 7 -CH3 H c2¾ 3- < CH30) -C6H4 C (0) 3133 CH CH c 7-0.3 H. Ca¾ 4- (CHsO) -C6H * C (O) 3134 CH CH c 7-CH3 H ¾¾ 2,3-. { CH30) a-C6H3 C (O) 3135 CH CH c 7-CH 3 H 2, - (CH 30) 3-C 6 H 3 C { 0) 3136 CH CH c 7 -CH3 H 'C2HS 3,4-lCH30 > 2-C6¾ C (O) 3137 CH CH c 7-CHj H Cj¾ 3,5-. { CH30) 2-C6H3 C (O) 3138 CH CH c 7 -CH3 H C2HS 3,4Í5- (CH30) 3-C6H2 C { 0) - - - - - - - - - 3264 CH CH CH H C6HS c6¾ 3- (C¾0) -C6H "C < 0] 3265 CH CH CH H C.HS CsH5 4-. { CH30) -C_H4 C (0) 3266 CH CH CH H CsHs CsHs 2,3 - (?? 3?)? - ae? 3 C (0) 3267 CH CH CH H C «HS C« Hs 2,4-. { GH30) j-C «H3 C (0) 3268 CH CH CH H c, ¾ CeHs 3,4-. { CH30) .- C6¾ C < 0) 3269 CH CH CH H CSH 5 CjHs 3,5-lCH 30) 2-C 6 H 3 C < 0) 3270 CH CH CH H CSHS CeHs 3,4,5- (a? 30) 3-? 6? 2 C (O) 3271 CH CH CK H CSHS 2- (CH30) -CsH4 CH, C (0) 3272 CH CH CH H C5H5 2- (CH30) -¾¾ ¾¾ C (O) 3273 CH CH CH H ce¾ 2- (C¾0 > - < ¼¾ C (O) 3274 CH CH CH H CgHj 2- (CH30) -Ci¾ 2- (CH3O) -Cf¾ C (O) 3275 CH CH CH H CsHs 2- (C% 0) - (¼¾ 3- (C¾0) -C3¾ C { 0) 3276 CH CH CH H C.HS 2- (CH30) -C.H4 4- (CH3O) -Ct1 C { 0) 3277 CH CH CH H C.H5 2- (CH3O) -C6H 2r3- (CH30) 2-C3H3 C (O) 3278 CH CH CH H c «¾ 2-. { CH30) -C6H4 2.4 ~ (CH30 -C6H3 C (O) 3279 CH 'CH CH H CfH5 2- (C¾0) -CeHí 3,4- (CH30) 2-C3H3 C (O) 3280 CH CH CH H Ce 2 2- (CH 3 O) -CeHi 3,5- (C330) 2-CsH3 C { 0) 3281 CH CH CH? C6H5 2- (CH30) -Ci¾ 3.4.5r (CH30) 3-C6H2 C { 0) 3282 CH CH CH H CSH5 3- (CH30) -Ce¾ CH3 C (0) 3283 CH CH CH H C5H5 3- (CH30) -¾¾ ¾¾ C (O) 3284 CH CH CH H C6H5 3- (CB30) -CeOt C6HS C < 0) 3285 CH CH CH H c6¾ 3- (C¾0) -C6H | 2-. { GH30} -'C6H4 C < 0) 3286 CK CH CH B CeH5 3-tCH30) -CiH4 3- (CH3O) -C6Ri C (O) 3287 CH CH CH H C6HS 3- (CH30 > -CeHi 4- (CH3O) -C & C (0) 3288 CH CH CH K C6HS 3- (CH30) -C6¾ 2.3- (C¾0) 2-C6H3 C (O) 3289 CH CH CH H Ci% 3-. { CH30) - < ¼¾ 2,4- (CT30) s-C6H3 C (O) 3290 CH CH CH H C »H5 3-ICH3O) -C6H4 3.4- (CH30) a-C6¾ C (O) 3291 CH CH CH H CiH $ 3- (CH3O) -CtH4 3.5 - (?? 30) 2-06? 3 C (O) 3292 CH CH CH H C "H5 3- (CH3O) -C5U4 3 4.5- (CH30) 3-C3¾ C (0) 3293 CH CH CH H CsH5 4- (CH3O) -CjHt CH3 C (O) 3294 CH CH CB H C6H5 4- (CH30) -CeHi CaHs C (O) 3295 CH CH CH H CsH5 4- (CH30) -C6H4 CiHs C < 0) 3296 CH CH CH H C6H5 4-. { CH30) -C6H4 2- (CH30) -C6H4 C (O) 3297 CB CH CH H CiH5 4-. { CH30) -C6H4 3- < C¾0) -C6H4 C (O) 3298 CH CH CH H CsHs 4- (CHjO) -C6H4 4- (CH30) -C6H4 C (O) 3299 CH CH CH H C6H5 4- (CH30) -C6H4 2.3- (CH30) 2-C6H3 C (O) - - - - - - - - - - 3387 CH CH CH 5-C1 CSH5 CeH5 2,3- (CH30) 2-C6H3 C (O) 3388 CH CH CH 5-C1 < ¼% CSH5 2,4- (CH, 0) 2-C6H3 C (O) 3383 CH CH CH 5-C1 C »H5 CtH5 3,4-. { CHjO) 2-CsB3 C (O) 3390 CH CH CH 5-C1 < ¼% CtH5 3,5-. { CH30) 2-CHs C < 0) 3391 CH CH- CH 5-C1 C6HS CgH5 3,4,5- < CH30) 3-Cs¾ C (0) 3392 CH CH CH 5-C1 CsHj 2- (CTjO) -CeH * C¾ C (O) 3393 CH CH CH 5-C1 C (Hs 2- (C¾0) -CeH * C2HS C <0) 3394 CH CH CH 5-C1 ¾% 2- (CHjO) - < ¼¾ C6HS C { 0) 3395 CH CH CH 5-C1 CsH5 2- < CH30) -C3H4 2- (CH3O) -C6¾ C (O) 3396 CH CH CH 5-C1 CgHs 2- (CH30) -CiH4 3- (CH30) -C6H4 C (O) 3397 CH CH CK 5-C1 ct¾ 2 ~. { CH30) -C6H1 4-. { CHjO) -C5H | CO) 3398 CH CH CH. 5-C1 ¾HS · 2- < CH30) -C3H4 2 / 3-. { CH30) 2-C6Hj C (0) 3399 CH CH CH 5-C1 CsH5 2- (CHsO) -C3H4 2,4- (C¾0) 2-CÍH3 C (0) 3400 CH CH CH 5-C1 CSH5 2- (CHjO) -C6H "3,4- (CH30.) 2-C" H3 C (0) 3401 CH GH CH 5-C1 c6 2 - (? 0) -06? 4 3.5-. { CH30 } 2-CsH3 C (O) 3402 CH CH CH 5-C1 C6HS 2- (CH3O) - < ¼H4 3.4.5- (CHsOb-CeHj C (0 > 3403 CH CH CH 5-C1 3- (CH30) -C3H4 CH3 C (O) 3404 CH CH CH 5-C1 3- (CH30) -C6H4 C2H5 C { 0) 3405 CH CH CH 5-C1 3- (P¾0) -C3¾ C5H5 C (O) 3406 CH CH CH 5-C1 cs¾ 3- (CH30) -C3H 2- (CH30) -CgHi C { 0) 3407 CH CH CH 5-C1 C6H5 3- < CH30) -C.H4 3- (CH3O) -C_H4 C (O) 3408 CH CH CH 5-C1 C¾H5 3- (CH3O) -CsH | 4-. { 30) -? 6? 4 C (O) 3409 CH CH CH 5-C1 CeH5 3-. { CH3O) -CSH4 2.3-. { CH30) s-C6H3 C (0) 3410 CH CH CH 5-C1 CcHs 3-. { CH30) -C5H4 2.4- (CH30) 2-C6H3 C (O) 3411 GH CH CH 5-C1 C5H5 3- (CH3) -C¼H4 3.4- (CH30) 2-CeH3 C (O) 3412 CH CH CH 5-C1 CBHJ 3- (CH30) -C6H 3.5- (C¾0) 2-C6H3 C { 0) 3413 CH CH CH 5-C1 C.HS 3- (CH30> -C6Hi 3,4,5- (Cai30) 3-C6Ha C (O) 3414 CH CH CH 5-C1 C1H5 4- (CH3O) -CeB CH3 C (O) 3415 CH CH CH 5-C1 C »Hs 4- (CHjO) -C6H4 ¾HS C (O) 3416 CH CH CH 5-C1 C.¾ 4- (CH30) -C6Ht C6H5 C (0 > 3417 CH CH CH 5-C1 CsH5 4- (CHjO) -C1H4 2- (CH3O) -CiH4 C (0) 3418 CH CH CH 5-C1 Ce¾ 4- (C% 0 > -CBH «3- (CMsO) -C6H4 C {0) 3419 CH CH CH 5-C1 4-. { C3i30) -CsH4 4- (CHjO) -¾¾ C { 0) 3420 CH CH CH 5-C1 ct¾ 4- (CHjO) -C (H4 2.3- <CH30) 2-C6H3 C (O) 3421 CH CH ca 5-C1 CSHS 4- (CH30) -CiH4 2,4- (CH30) 2-C6H3 C (0) 3422 CH CH CH 5-Cl C H H 5 4- (CH 3 O) -C t H 4 3,4- (CH 30) 2-C 6 H 3 C (O) - - - 3506 N CH CH H H CsHs 3- (C-H30 > -C6¾ C (O) 3507 N CH CH H H C B5 4-. { CH30) -Ce¾ C (O) 3508 N CH CH H H C.¾ 2,3-fCH30), - C «H3 C (O) 3509- N CH CH H H ¾% 2.4- (CH30) i-CeH3 C < 0) 3510 N CH CH H HHS 3.4-. { CH30) 2-C6H3 C (O) 3511 H CH CH H H CSH5 3, S- (CH30) a-C6H3 C (0) 3512 N CH CH H H CeHs 3,4,5- (CH 30) 3-C 6 H. CO) 3513 N CH CH H H 2- (CH30) -C_¾ CH3 C (0) 3514 H CH CH H H 2 ~ (CHjO) -C_¾ CjHs C (0) 3515 N CH CH H H 2- (CHsO) -C8H4 C «HS C (O) 3516 N CH CH H H 2- (CHjO) -C6HÍ 2- (C¾0) -C_H4 C (O) 3517 N CH CH H H 2- (CH30) -C6¾ 3- (CH30) -C6H4 C (O) 3518 N CH CH H H 2- (C3¾0) ~ C-H4 4- (C¾0) -C6H «C (0) 3519 N CH CH H H 2- (CH30) -C6¾ 2.3-. { CH30) 2-CiH3 C (0) 3520 N CH CH H H 2- < CH30) -CS¾ 2.4- (CH30) J-CÍH3 C (0) 3521 N CH CH H K 2- (CH30) -C6H4 3 (4- (CH30) 2-C «H3 C (O) 3522 N CH CH H 2- (C¾0) -C6H4 3.5- (CH30) _- C «H3 C (O) 3523 H CH CH H H 2-. { ? ¾0) -? 6? 4 3r, 5- < CH30 } 3-CsH2 C (O) 3524 N CH CH H H 3- (C¾0) -C6H «CH3 C (O) 3525 N CH CH H H 3- (CH30) - ¿Cj¾ C (O) 3526 N CH CH K H 3- (CH30) -C £ Hi ¾¾ C (O) 3527 N CH. CH H H 3- (CHjO) -C6H4 2- (CHjO> -CgHi C (O) 3528 N CH CH H H 3- (C¾0) -C 6 H, 3- < CH30) -C £ H < C { 0) 3529 N CH CH H H 3-. { C¾0) -CÍH4 4- (CH30) -Cs¾ C (0) 3530 N CH CH H H 3- (C¾0) -Ct¾ 2,3-. { CH30) 2-C6H3 CÍO) 3531 N CH CH H H 3- < ? ¼0) - < ¾¾ 2,4- (CH30) 2-C6¾ C (0) 3532 N CH CH H H 3- < CH30) -C «H, 3.4- < CH30) a-C € Hj C (0) 3533 N CH CH H H 3- (CH30) -CiH «3,5- (C¾0) 2-Ce¾ C (0) 3534 K CH CH H H 3- (C¾0) -Cs¾ 3,4,5- (CH30) 3-C6H, C (O) 3535 N CH CH H H 4- (CH30) -C6H4 CH3 C (O) 3536 N CH CH H H 4- (CH30) -C_H «C2H5 C (0) 3537 H CH CH H H 4-. { CH30) -C6H4 C € HB C { 0) 3538 N CH CH H H 4- (CHjO) -C3¾ 2- (CH30) -CsHi C (0) 3539 N CH CH H H 4- < C¾0 > -C1H «3- < CH30) -C6H4 C (0) 3540 N CH CH H H 4- < CH30) -C < H «4- (CH30) -C6Hi C (0) 3541 N CH CH H H 4- < CH30) -C6¾ 2.3- (CH30) s-C6H3 C (0) - - - - - - 3750 CH CH N H H CfiH5 2,3- < CH30) a-C6H3 C (O) 3751 CH CH N H H C5H5 2, 4-. { CH30) 2-CtH3 C (O) 3752 CH CH N K H CfH5 3.4- (CH30 > 2-C6H3 C (OJ 3753 CH CH N H H CgH5 3.5- (C¾O -C (H3 C {0) 3754 CK CH N H H Cs¾ 3,4,5- (CH30) 3-CeH2 C (O) 3755 CH CH N H H 2- (CH30) -CiH «C¾ C (0.). 3756 CH CH N H R 2- (CH30) -C6H4 ¾¾ C (OJ 3757 CH CH H H H 2- < C% C »-Ce¾ CiH5 C (O) 3758 CH CH N H H 2- (a¾0) -c6¾ 2-. { CH30) -C3H4 C (O) 3759 CH CH N H H 2- (C¾0) -C 3 H 4 3- (CH 30) -C 6 C (0) 3760 CH CH N H H 2- (C¾0) -C5¾ 4- (CH30) -C6H4 C (0) 3761 CH CH N H H 2- (CH30 > -C3¾ 2,3- (CH30) 2-C.H3 C (0) 3762 CH CH N H H 2- (C¾0> -C6¾ 2, 4- (CH30) 2-CtH3 C (O) 3763 CH CH N H H 2- (C¾0) -C 6 H 4 3,4- (CH 30) 2-C 5 H 3 C (0) 3764 CH CH N H H 2- (C¾0) -C3¾ 3.5- (CH30) j ~ CsH3 C (O) 3765 CH CH N H H 2- (CH30) -C6Hi 3, 4.5- (CH3Ob-C; H2 C (O) 3766 CH CH N H H 3- (C¾0) -C6¾ CH3 C (0) 3767 CH CH N H H 3- (a? 30) - (¼? 4 ¾¾ C (0) 3768 CH CH N H H 3- (C¾0) -Cs¾ C6Hs C (O) 3769 CH CH N H K 3- (C¾0) -C6H4 2- iCH30) -CeH4 C { 0) 3770 CH CH N H H 3- (CH30) -C6H4 3- (CH30) -C6¾ C (O) 3771 CH CH N H H 3- (CH30) -C8H | 4- (CHjO) -C6H4 C (0) 3772 CH CH N H H 3- (C¾0) -C6¾ 2.3- (CH30> 2-CiH3 C (0) 3773 CH CH N? H 3- (CH 30) -CÍHÍ 2,4- < C¾0) 2-C_H3 C (0) 3774 CH CH N H H 3- (CM30) -C6¾ 3.4- (CH30) 2-CsH3 C (0) 3775 CH CH N H H 3- (C¾0.}. -C3¾ 3.5- (C¾0) 2-CeH3 C (0) 3776 CH CH N H H 3- (C¾0) -CS «« 3,4,5-ICHJO) 3-CSHJ C (0 > 3777 CH CH N H K 4- (CH 30) -C 3 H CH, C (0) 3778 CH CH N H H 4- (CH30) -C5¾ C2H5 C (0) 3779 CH CH N H a 4-. { CH30) -C6H4 C { 0) 3780 CH CH N H H 4- (CH30) -C ^ Ji 2- < CH30) -C5H, C (0) 3781 CH CH N H H 4- (CS30) -CSH 3- (CH30) -C6Hi C (0) 3782 CH CH N H? 4- (C¾0) -C6H "4 ~ (CH30) -C6H4 C (0) 3783 CH CH N H H 4- | CH30) -C6¾ 2.3- (CH30) 3-C6H3 C (0) 3784 CH CH K H H 4- (CHjO) -C6H * 2.4-. { CH30 > 2-C6H3 C (0) 3785 CH CH N H H 4- (CHjO) -C3H4 3,4- (CH30) 2-C6Hj C (0) 3786 CH CH N H H 4- (CHjO) ~ C6H «C (O) 3787 CH CH N H H 4- (C¾0) -C * H * 3,4,5- (CH30) 3-C6¾ C (O) 3788 CH CH »H H 2,3- < C! ¾0) 2- CH3 C (O) 3789 CH CH N H H 2.3- < C% 0) a- Ca¾ C (O) 3790 CH CH N H H 2.3- (C¾0) a- CB¾ C (O) cs% 3791 CH CH N H H 2.3- (C% O) a- 2- (CH30) -Ct¾ C (O) < ¼¾ 3792 CH CH N H H 2.3-. { C% 0) a- 3- (CH30) -Ct¾ C (O) C6H3 3793 CH CH NHH 2.3- (CH30.} A- 4- < CH30) -C6¾ C (O) ¾¾ 3794 CH CH NHH 2.3- (O¾0.}. - 2,3- { CH30) 2-CeH3 C { 0) Ce¾ 3795 CH CH NBH 2,3-lCH 30) a- 2 4- [CHJ0) aC «H3 C (O) c.¾ 3796 CH CH RHH 2,3- (CHjO) 2- 3, - (CHsO - Csft C (O) C6H3 3797 CH CH NHH 2.3- <CHjO> a- 3.5 - (?? 30) 2-¾¾ C (O) 3798 CH CH NHH 2.3- (C¾0.). I- 3.4.5- (CH30) 3-C ¾ C 0 0) CH, 3799 CH CH NHH 2.4- (C% O) 3- CH3 C (O) C «H3 3800 CH CH H? H 2.4- < C¾0) j- C2Hs C (0) < ¼ H, 3801 CH CH N H H 2.4- (C¾0> 2- CeHs C { 0) CS¾ 3802 CH CH H H H 2.4-. { CHjO - 2- (CHjO) -C «Hi C (O) 3803 CH CH NHH 2.4- (CH30) 2- 3- (qij0) -¾¾ CtO) CsH3 3804 CH CH HHH 2.4 ~ (CH30 > 2- 4- (GHjO) -C6H4 C (0) C6H3 - - 3840 CH CH N H H 3,4,5- (CH30) 3C6H2 3,4- (CH30) 2C6H3 C (0) 3841 CH CH N H H 3.4.5- (CH30) 3-C6H2 3.5- (CH30) 2C6H3 C (O) 3842 CH CH N H H 3A5- (CH30) 3-C6H2 3A5- (CH30) 2C6H2 P (0) Analogously, according to the general procedure F, it is also possible to prepare the following compounds according to the invention (examples numbers 3843 to 6250): Examples numbers 3843-5051: A, C, D, R, Rl, R6, R8 and X are, in each case, as defined in examples Nos. 2635 to 3842 above, and, in each case, is S (O): Examples Nos. 5052-6260: A, C, D, R, R1, R6, R8 and X are, in each case, as defined in examples Nos. 2635 to 3842 above, and, in each case, S02.

Result of pharmacological tests In vitro tests of selected tumor models show the following pharmacological activities. Example 1: Antiproliferative Properties Substances D-70260, D-70744, D-80815, D-80816 and D-80819 (Examples C2.3, D4, F2, F3 and F4) were examined for their antiproliferative activity in an assay of proliferation (Scudiero et al., Cancer Res., 48: 4827-33, 1987) using established tumor cell lines. The test used determines the activity of mitochondrial dehydrogenase and allows the cell vitality to be determined and indirectly the number of cells. The cell lines used are human HeLa / KB cell lines (CCL17), SK-OV-3 (HTB77), MCF-7 (HTB22) and the murine leukemia cell line L1210 (CCL219). These are cell lines that are very well characterized and established that are obtained from ATCC and grown. The results are summarized in table 1, and show a highly potent antiproliferative action of the substances D-70260, D-70744 and D-80816 (examples C2.3, D4 and F3). In contrast, structurally related compounds D-80815 and D-80819 (examples D2 and F4) show no significant action. Consequently, there are defined relationships in terms of structure and activity.

Table 1. Antiproliferative activity of different derivatives in the XTT toxicity test with HeLa / B, SK-OV-3, MCF-7 and L1210 cell lines. What is established is the percent inhibition at a concentration of 3.16 g / ml.

Figure 1 is a graphical representation of the antiproliferative activity that depends on the concentration of D-80816 (example F3) in the XTT cytotoxicity test with HeLa / KB, SK-OV-3, MCF-7 and L1210 cell lines (TO) .

Example 2: Effect of D-80816 (example F3) on the hollow fiber model in vivo To determine the availability and efficacy in the animal model (nude mouse), the HeLa / KB, MCF-7 and L1210 cell lines are cultured in implanted hollow fibers ip or s.c. (Hollingshead et al., Life Sciences 57, 131-41, 1995). Test substance D-80816 is administered four times in a dose of 100 mg / kg i.p. After the end of the treatment on day 5, the fibers are extracted and the viability of the cells of the tumor cells obtained is determined, using the XTT assay. D-80816 shows a maximum inhibition of 100% for all cell lines and implantation sites, with a general toxicity of LD50 > 1,000 mg / kg (i.p.).

Table 2. In vivo activity of D-80816 (dose: 4x 100 mg / kg, i.p.) in the following hollow fiber test with Hela / KB, MCF-7 and L1210 tumor cell lines.

Example 3: Specific action in the cell cycle of D-80816 in the RKOp27 model The RKOp27 cell system (M. Schmidt et al., Oncogenel9 (20): 2423-9, 2000) is used as a model to examine the specific action in the cell cycle. RKO is a line of human colon carcinoma in which the cell cycle inhibitor p27Kipl is expressed induced by the ecdysone expression system, which results in a cell cycle suppression specifically in Gl (figure 2). A substance with nonspecific action inhibits proliferation regardless of whether the RKO cell is suppressed or not in Gl. In contrast, cell-cycle-specific substances such as, for example, tubulin inhibitors are only cytotoxic when the cells are not suppressed and are undergoing the cell cycle. Here, D-80816 shows a cell-cycle-specific action, ie, a concentration-dependent antiproliferative action that can only be measured in non-induced cells which are not suppressed in Gl of the cell cycle (Figure 3). Accordingly, the assumption can be made that there is a defined mechanism of molecular action of D-80816 and its derivatives. Figure 2 shows a schematic representation of the induced expression of p27 / kipl leading to deletion in the cell cycle in Gl and the treatment sequence of +/- inducer cells (muristerone A) and the test substance. Figure 3 shows the antiproliferative effect of D-80816 (example F3) on RKO colon carcinoma cells suppressed in the Gl phase of the cell cycle (induced) or that underwent in the cell cycle, that is, they proliferated exponentially.

Description of the methods used XTT test for cellular dehydrogenase activity The adherently growing tumor cell lines HeLa / KB, SK-OV-3, MCF-7, L1210 and RKO were cultured under standard conditions in a fumigation incubator a 37 ° C, C02 5% and 95% atmospheric humidity. On day 1 of the experiment, the cells are detached using trypsin / EDTA and pelleted by centrifugation. Subsequently, the cell pellet is resuspended in the respective culture medium and the appropriate cell count is performed and reacted in 96-well microtiter plates. The plates are then grown overnight in the fumigation incubator. The test substances are prepared as concentrated solutions 10 m in DMSO and, on day 2 of the experiment, they are diluted to the appropriate concentrations using culture medium. The substances in the culture medium are then added to the cells and incubated in the fumigation incubator for 45 h. Cells which have not been treated with the test substance are used as a control. For the XTT assay, 1 mg / ml of XTT (31- (1-phenylaminocarbonyl) -3,4-tetrazolium] bis (4-methoxy-6-nitro) benzenesulfonic acid) dissolved in RPMI-1640 medium is dissolved without phenol red Additionally, a solution of 0.383 mg / ml of PMS (N-methyldibenzopyrazine methylsulfate) in phosphate buffered saline (PBS) is prepared. On the day of the experiment, 4.5 μ? / ???? of the XTT-PMS mixture on cell plates which in the meantime have been incubated with the test substances for 45 h. For this, a little before its use, the XTT solution is mixed with the PMS solution in a 50: 1 ratio (v.-v). The cell plates are then incubated in the fumigation incubator for an additional 3 h and the optical density (OD490 nm) is determined in a photometer. By means of the determination of the OD490 nm, the percentage of inhibition in relation to the control is calculated and semi-logarithmically plotted in the form of a concentration versus activity curve. The IC50 is calculated by means of a regression analysis from the concentration versus activity curve using the Graphpad program.

Determination of antiproliferative activity in the hollow fiber model in vivo HeLa / KB, MCF-7 and L1210 tumor cell lines are introduced into hollow fibers made of poly (vinylidene fluoride) (5 x 10 cells / ml) and transplanted into the physiological compartments of athymic mice (intraperitoneal, ip or subcutaneous, sc) | In each test animal a total of 6 hollow fibers (3 ip and 3 sc) containing the tumor cell lines in question were transplanted. A group of 6 animals is treated with the test substance (i.p., lx daily for a total of 4 days) (is that correct?). Animals treated only with the hair solvent serve as a control or control group. One day after the last substance application, the hollow fibers are removed. The number of vital, metabolically active cells for each hollow fiber is determined using the XTT assay (see above). From this, the antitumor activity of the test substance is determined in% inhibition relative to the control.

Cell cycle analysis using the RKOp27 model The assay is carried out in 96-well plates. By inducible expression of p27kipl, the growth of the cells is completely suppressed, but the cells do not die. When comparing the efficacy on induced and non-induced cells, it is possible to draw conclusions regarding the mechanism of action (cell cycle specificity) of the therapeutic substances. The non-induced cells are seeded in a cell count which is approximately four times larger, since, in comparison with non-induced cells, there are no further divisions during the assay (2 x 10 4 cells / well induced, approximately 0.6 x 10 4 cells / well not induced). The controls are untreated cells (+/- induction). The induction is carried out using 3 μ? of muristerone? On day 1, the cells are seeded (+/- muristerone A) and incubated at 37 ° C for 24 hours. On day 2 the test substance is added (control with DMSO) and the samples are incubated at 37 ° C for 48 hours before the standard XTT assay is carried out (see above). The compounds according to the invention can be used as medicaments in the treatment of diseases, in particular tumor diseases, in mammals, particularly in man. The administration can be oral, topical or parenteral (i.m., i.v., s.c.) in the appropriate administration form. Examples of suitable administration forms that may be mentioned are: Example I Tablet with 50 mg of active compound Composition: (1) Active compound 50.0 mg (2) Lactose 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinyl pyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg Sum: 215.0 mg Preparation: Mix (1), (2) and (3) and granulate using an aqueous solution of (4). Mix (5) with the dry granules. This mixture is compacted to tablets.

Example II Capsules with 50 mg of active compound Composition: (1) Active compound 50.0 mg (2) Dry corn starch 58.0 mg (3) Powdered lactose 20.0 mg (4 mg magnesium stearate 2.0 mg Sum: 160.0 mg Preparation It is ground (1) with 3). With vigorous mixing, this mixture is added to the mixture of (2) and (4). This pulverized mixture is applied as filling in a machine to fill c capsules, in hard gelatin capsules of size (3).

Claims (7)

1. A compound of the formula I wherein R 1 is hydrogen, aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, heteroaryl of 1 to 13 carbon atoms which contains at least 1 to 4 N, NH, 0 or S as ring members and is unsubstituted or substituted wholly or partially by identical or different substituents, cycloalkyl of 3 to 8 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, or alkyl from 1 to 20 carbon atoms straight or branched chain which is unsubstituted or substituted completely or partially by identical or different substituents; A, B, C or D independently of each other are a nitrogen atom or a carbon atom substituted by R2-R5; R2, R3, R4 and R5 independently of each other are a pair of free electrons (if the binding partner A, B, C or D are a nitrogen atom), hydrogen, halogen, cyano, nitro, hydroxyl, alkyl of 1 to 6 carbon atoms straight or branched chain, alkyl of 1 to 6 carbon atoms straight or branched chain which is substituted by one or more halogen atoms, alkoxy of 1 to 6 carbon atoms straight or branched chain, alkoxy from 1 to 6 carbon atoms straight or branched chain which is substituted by one or more halogen atoms, straight or branched chain alkylenedioxy of 1 to 6 carbon atoms, alkylcarbonyloxy of 1 to 6 carbon atoms, alkoxycarbonyloxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, carboxyl, alkyl carboxylate of 1 to 6 carbon atoms, carboxamide, N- alkylcarboxamide of 1 to 6 carbon atoms or, N, N-di-alkylcarboxamide of 1 to 6 carbon atoms, alkoxy (of 1 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, wherein the two radicals of 1 to 6 carbon atoms together can form a ring which optionally contains one or more of NH, N-alkyl of 1 to 6 carbon atoms, 0 or S, aryl of 6 to 14 carbon atoms, aryloxy of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkoxy ( from 1 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, hydroxyl, wherein the two directly adjacent radicals can be attached to each other; R6 is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, heteroaryl of 1 to 13 carbon atoms which contains at least 1 to 4 of M, H, O and S as ring members and is unsubstituted or substituted completely or partially by identical or different substituents, cycloalkyl of 3 to 8 carbon atoms, which is unsubstituted or substituted wholly or partially by identical or different substituents, alkyl of 1 to 20 carbon atoms of straight or branched chain which is unsubstituted or substituted wholly or partially by identical or different substituents, wherein the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, carboxyl, alkyl of 1 to 6 carbon atoms which is replaced by one om or more identical or different halogen atoms, alkoxy of 1 to 6 carbon atoms which is substituted by one or more identical or different halogen atoms, alkenyl of 2 to 6 carbon atoms of straight or branched chain, alkynyl of 2 to 6 carbon atoms of straight or branched chain, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms of straight or branched chain, straight or branched chain alkylenedioxy of 1 to 6 carbon atoms, alkoxy (of 1 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkoxy (of 1 to 4 carbon atoms) -alkyl of 1 to 6 carbon atoms; X is a carbonyl group (C = 0), sulfoxide (S = 0) or sulfonyl (S02); Y is an oxygen atom or a nitrogen atom substituted by the radical R7 (NR7), wherein: R7 is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted completely or partially by identical or different substituents, heteroaryl from 1 to 13 carbon atoms, which contains at least one to four of N, NH, O or S as ring members and is unsubstituted or substituted completely or partially by identical or different substituents, cycloalkyl of 3 to 8 atoms of carbon which is unsubstituted or substituted wholly or partially by identical or different substituents, straight or branched chain alkyl of 1 to 20 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, wherein Identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms, carboxyl, alkyl of 1 to 6 carbon atoms which is substituted by one or more identical or different halogen atoms, alkoxy of 1 to 6 carbon atoms which is substituted by one or more atoms of identical or different halogen atoms, straight or branched chain 2 to 6 carbon alkenyl, straight or branched chain alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms straight or branched chain carbon, straight or branched chain 1 to 6 carbon alkylenedioxy, alkoxy (1-6 carbon atoms) -alkyl of 1 to 6 carbon atoms, monoalkylamino of 1 to 6 carbon atoms of linear or branched chain, dialkylamino of 1 to 6 carbon atoms straight or branched chain wherein the two radicals of 1 to 4 carbon atoms together can form a ring which optionally contains one or more of NH, N-alkyl of 1 to 6 carbon atoms, 0 or S, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkoxy (of 1 to 4 atoms) carbon) -alkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms or alkoxycarbonyl of 1 to 6 carbon atoms; n is 0 or 1, with the proviso that if n = 0, Z is a carbon atom substituted by the radical R8 (C-R8) wherein R8 is aryl of 6 to 14 carbon atoms which is unsubstituted or fully or partially substituted by identical or different substituents, heteroaryl of 1 to 13 carbon atoms which contains at least 1 to 4 of N, NH, O or S as ring members and is unsubstituted or substituted wholly or partially by substituents identical or different, cycloalkyl of 3 to 8 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents, straight or branched chain 1 to 20 carbon atoms, which is unsubstituted or substituted or partially by identical or different substituents, wherein the identical or different substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, alkyl of 1 to 6 carbon atoms, oxy of 1 to 6 carbon atoms, carboxyl, alkyl of 1 to 6 carbon atoms which is substituted by one or more identical or different halogen atoms, alkoxy of 1 to 6 carbon atoms which is substituted by one or more identical or different halogen atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, straight or branched chain alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 6 atoms straight-chain or branched carbon, straight-chain or branched-chain alkylenedioxy, straight-chain or branched-chain alkylthio, C 1-6 alkylsulfinyl with 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, arylthio of 6 to 14 carbon atoms, arylsulfinyl of 6 to 14 carbon atoms, arylsulfonyl of 6 to 14 carbon atoms, alkoxy (of 1 to 6 carbon atoms) -alkyl 1 to 6 carbon atoms, straight or branched chain monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms straight or branched chain wherein the two radicals of 1 to 4 carbon atoms together can form a ring which optionally contains one or more of NH, N-alkyl of 1 to 6 carbon atoms, O or S, aryl of 6 to 14 carbon atoms, aryloxy of 6 to 14 carbon atoms, aryl (of 6 to 14) carbon atoms) -alkyl of 1 to 6 carbon atoms, aryl (of 6 to 14 carbon atoms) -alkoxy (of 1 to 4 carbon atoms) -alkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to S carbon atoms, mono-N-alkylcarbonylamino of 1 to 6 carbon atoms of straight-chain or amide, di-N, N-alkylcarbonylamino of 1 to 6 carbon atoms straight or branched chain, mono-N-alkoxycarbonylamino of 1 to 6 carbon atoms straight or branched chain, di-N, N-alkoxycarbonylamino of 1 to S carbon atoms of straight or branched chain, N-alkyl (of 1 to 6 carbon atoms) -carbonylamino-N-alkylamino of 1 to 6 carbon atoms, straight or branched chain, or N-alkoxy (from 1 to 6 carbon atoms) -carbonylamino-N-alkylamino of 1 to 6 carbon atoms straight or branched chain; and where, if n = 1, Z is a nitrogen atom; or a tautomer, a stereoisomer, a mixture or a pharmaceutically acceptable salt thereof.

2. The compound as described in claim 1, characterized in that R1 is hydrogen, R2, R3, R4 and R5 independently of each other are hydrogen, halogen or alkoxy of 1 to 6 carbon atoms, R6 is alkyl of 1 to 20 atoms of straight or branched chain carbon which is unsubstituted or substituted wholly or partially by identical or different substituents or is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by substituents identical or different from the group consists of alkoxy of 1 to 6 carbon atoms and halogen, Y is an oxygen atom or the radical N-R7, wherein R7 is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by substituents identical or different, X is carbonyl (C = 0), Z is a nitrogen atom and n = 1.

3. The compound as described in claim 1, characterized in that R1 is hydrogen, R2, R3, R4 and R5 independently in if they are hydrogen, halogen or alkoxy of 1 to 6 carbon atoms, R6 is straight or branched chain alkyl of 1 to 20 carbon atoms which is unsubstituted or substituted wholly or partially by identical or different substituents or is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by substituents identical or different from the group consisting of alkoxy of 1 to 6 carbon atoms and halogen, n = 0, Z is the radical C-R8, in where R8 is aryl of 6 to 14 carbon atoms which is unsubstituted or substituted wholly or partially by substituents identical or different from the group consisting of alkoxy of 1 to 6 carbon atoms and halogen, and X is carbonyl (C = 0 ).

4. The compound as described in any of claims 1 to 3, for use as a medicament.

5. The use of a compound as described in any of claims 1 to 3 for the elimination of tumor disorders in mammals, in particular in man.

6. A medicament comprising at least one compound as described in any of claims 1 to 3 together with auxiliaries, diluent, are pharmaceutically acceptable carriers.

7. A method for preparing compounds of the formula I, wherein A, B, C, D, R1, R2, R3, R4, R4, R5, Y, Z and n are as described in claim 1, method is characterized in that: b) the ketone is reacted formula with aa) oxime, or bb) hydrazine derivative H2N-NH-R7 wherein R7 is as described in claim 1, and the resulting product is cyclized with an activated carbonyl, a sulfoxide or sulfonyl derivative or is reacted with: ce) a phenylacetic acid derivative XI-CO-CH2-R8, wherein XI is a suitable leaving group, such as halogen or alkoxy of 1 to 2 carbon atoms, and R8 is as defined in claim 1, followed by cyclization in the presence of base.